Paraoxonase 1 polymorphisms and survival

Abstract

The antioxidant enzyme paraoxonase 1 (PON1) has previously been suggested to confer protection against coronary heart disease (CHD), one of the main causes of death in the Western world. Two coding polymorphisms, 55M/L and 192Q/R, and a promoter variant, À107C/T, has been extensively studied with respect to susceptibility to CHD. In this study, we have investigated the impact of these three polymorphisms on mortality using a sample of 1932 Danish individuals aged 47-93 years, previously used in gene-longevity studies. A cross-sectional study comparing the genotype distribution of the three polymorphisms separately as well as the haplotype distribution in different age groups did not reveal any difference. However, a longitudinal follow-up study on survival in the same sample indicated that 192RR homozygotes have a poorer survival compared to QQ homozygotes (hazard rate: 1.38, P ¼ 0.04). We hereafter used an independent sample of 541 Danish individuals from the oldest cohort and confirmed the initial findings (hazard rate: 1.38, P ¼ 0.09). In both samples, the effect was most pronounced in women. Using self-reported data on ischemic heart disease to evaluate the impact of the PON 192Q/R polymorphism on susceptibility to CHD, we found only a nonsignificant trend of 192RR homozygosity in women being a risk factor. Our results thus indicates that PON1 192RR homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD.

Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population

“…However, these findings were not always consistent. 22,23 In our study, we did not replicate any of the reported associations, but instead identified association at rs854563 (P CMH ¼1.92Â10 À04 ), which lies within the same LD block as the L55M variant. rs854563 showed stronger association than the L55M variant itself or the haplotype tagged by both SNPs.…”

Genetic Association Analysis of Human Longevity in Cohort Studies of Elderly Subjects: An Example of the PON1 Gene in the Danish 1905 Birth Cohort

“…We present our results on genotype-based analysis in Table 2, where, as described in methods, risk and frequency parameters are estimated for each genotype against the reference. Although only a subsample was used, our model detected PON1 192 Q/Q and Q/R genotypes as of potential influence (P ¼ 0.062 for Q/R and P ¼ 0.076 for Q/Q genotypes), a result consistent with that of Christiansen et al (2004). In Figure 2, we show the observed and the estimated genotype frequency patterns for all genotypes at the three loci.…”

“…Recent association studies are increasingly emphasizing the important roles that genes may play in affecting human survival at advanced ages (Bonafe et al 2002;Christiansen et al 2004;Bellizzi et al 2005;Hurme et al 2005). Further studies using efficient analytical tools are needed.…”

“…Recently, PON1 gene polymorphisms have been found to affect human survival (Bonafe et al 2002;Christiansen et al 2004). In the study by Christiansen et al (2004), three SNPs in the PON1 gene (two in the coding region, amino acids M55L and Q192R, and one in the promoter region, C-107T) were genotyped. Data analysis using the Cox regression model revealed a strong protective effect of the 55M/L genotype and an increased risk of death for carriers of the 192R/R genotype in females (a relative risk of 1.38).…”

“…In this case, the study aims at investigating the genetic effect on human survival at extreme ages, an important topic nowadays because of the largely increased mean life span in the developed countries (Vaupel et al 1998). In the literature, association studies using followup design on oldest-old subjects such as nonagenarians (Christiansen et al 2004;Hurme et al 2005) and centenarians (Blanche et al 2001;Louhija et al 2001) have already been conducted. With the collected genotype and survival information, traditional statistical methods have been employed for single-locus analysis, for example, frequency comparison using a simple x 2 -(trend) test or estimating genotype relative risk using the traditional Cox regression model.…”